PAX1 is essential for development and function of the human thymus. Sci Immunol 2020 Feb 28;5(44)
Date
03/01/2020Pubmed ID
32111619Pubmed Central ID
PMC7189207DOI
10.1126/sciimmunol.aax1036Scopus ID
2-s2.0-85081071846 (requires institutional sign-in at Scopus site) 54 CitationsAbstract
We investigated the molecular and cellular basis of severe combined immunodeficiency (SCID) in six patients with otofaciocervical syndrome type 2 who failed to attain T cell reconstitution after allogeneic hematopoietic stem cell transplantation, despite successful engraftment in three of them. We identified rare biallelic PAX1 rare variants in all patients. We demonstrated that these mutant PAX1 proteins have an altered conformation and flexibility of the paired box domain and reduced transcriptional activity. We generated patient-derived induced pluripotent stem cells and differentiated them into thymic epithelial progenitor cells and found that they have an altered transcriptional profile, including for genes involved in the development of the thymus and other tissues derived from pharyngeal pouches. These results identify biallelic, loss-of-function PAX1 mutations as the cause of a syndromic form of SCID due to altered thymus development.
Author List
Yamazaki Y, Urrutia R, Franco LM, Giliani S, Zhang K, Alazami AM, Dobbs AK, Masneri S, Joshi A, Otaizo-Carrasquero F, Myers TG, Ganesan S, Bondioni MP, Ho ML, Marks C, Alajlan H, Mohammed RW, Zou F, Valencia CA, Filipovich AH, Facchetti F, Boisson B, Azzari C, Al-Saud BK, Al-Mousa H, Casanova JL, Abraham RS, Notarangelo LDAuthor
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Branchio-Oto-Renal SyndromeEpithelial Cells
Humans
Infant
Male
Paired Box Transcription Factors
Severe Combined Immunodeficiency
Thymus Gland
